Method for dispensing a polymerizable monomer adhesive

ABSTRACT

This invention generally relates to a method of dispensing an adhesive material using an applicator comprising: a body having a cavity; at least one breaking member integral with the body and having a surrounding gap, the breaking member deflectable into the cavity and having a first engagement member; an annular housing movable with respect to the body and having a second engagement member complementary with the first engagement member, the first and the second engagement members being cooperatively engageable; a reservoir secured to body and having applicator means; a retaining member between the body and reservoir; and a frangible container of adhesive material disposed within the cavity; moving the annular housing relative to the body from a first position to a second position where the engagement members are cooperatively engaged; deflecting the breaking members and breaking the frangible container; and squeezing the reservoir and dispensing adhesive material.

CROSS REFERENCE TO RELATED APPLICATIONS

This divisional application claims the benefit of parent applicationSer. No. 11/565,022, filed Nov. 30, 2006, which is published as US2008/0131190 A1, now U.S. Pat. No. 8,118,508.

FIELD

The present invention relates to a dispenser such as an adhesiveapplicator device, in particular, an adhesive applicator device forapplying/dispensing a polymerizable adhesive composition.

BACKGROUND

Monomer and polymer adhesives are used in both industrial (includinghousehold) and medical applications. Included among these adhesives arethe 1,1-disubstituted ethylene monomers and polymers, such as theα-cyanoacrylates. Since the discovery of the adhesive properties of suchmonomers and polymers, they have found wide use due to the speed withwhich they cure, the strength of the resulting bond formed, and theirrelative ease of use. These characteristics have made theα-cyanoacrylate adhesives the primary choice for numerous applicationssuch as bonding plastics, rubbers, glass, metals, wood, and, morerecently, biological tissues.

It is known that monomeric forms of α-cyanoacrylates are extremelyreactive, polymerizing rapidly in the presence of even minute amounts ofan initiator, including moisture present in the air or on moist surfacessuch as animal (including human) tissue. Monomers of α-cyanoacrylatesare anionically polymerizable or free radical polymerizable, orpolymerizable by zwitterions or ion pairs to form polymers. Oncepolymerization has been initiated, the cure rate may be very rapid.

Medical applications of 1,1-disubstituted ethylene adhesive compositionsinclude use as an alternate or an adjunct to surgical sutures and/orstaples in wound closure, as well as for covering and protecting surfacewounds such as lacerations, abrasions, burns, stomatitis, sores, minorcuts and scrapes, and other wounds. When an adhesive is applied tosurfaces to be joined, it is usually applied in its monomeric form, andthe resultant polymerization gives rise to the desired adhesive bond.

However, due to the need to apply the adhesive or sealant material inits monomeric form, and due to the rapid polymerization rate of themonomers, it has been very difficult to design effective andcommercially viable applicators and/or dispensers. Such applicatorsand/or dispensers must balance the competing requirements that themonomer not prematurely polymerize, that the monomer be easily applied,that the monomer polymerize at a desired rate upon application, and thatthe sanitary and/or sterile properties of the monomer and applicator bemaintained.

Problems with known applicators and/or dispensers include, for example,the adhesive or sealant material being fed from the applicator device bygravity only. Such gravity feed methods may not allow for desiredcontrol over the flow of the adhesive or sealant material from theapplicator device during use. Furthermore, known applicators/dispensersmay not allow for fine control over and placement of the adhesive orsealant material at the time of use.

SUMMARY

The above needs are addressed by providing applicators and dispensersthat permit economical and efficient use of adhesive or sealantcompositions. In embodiments applicators and/or dispensers are providedthat are user friendly.

In one embodiment, an applicator device for dispensing a polymerizableadhesive material is provided. The applicator device comprises a bodyportion comprising a closed proximal end and an open distal endproviding a cavity. The cavity is sized to accept a frangible containerhaving a polymerizable adhesive material. At least one breaking memberis integral with the body portion and each breaking member has asurrounding gap. The at least one breaking member is at least partiallydeflectable into the cavity and each breaking member has a firstengagement member. An annular housing is movable with respect to thebody portion and has a second engagement member complementary with theat least one first engagement member, the first and the secondengagement member being cooperatively engageable with each other. Areservoir is secured to the open distal end of the body portion, thereservoir having applicator means. A retaining member is located betweenthe body portion and the reservoir. When the annular housing is movedrelative to the body portion from a first position where the first andthe second engagement members are not cooperatively engaged with eachother, to a second position where the first and the second engagementmembers are cooperatively engaged with each other, at least a portion ofthe breaking member is deflected into the cavity, breaking or piercingthe frangible container and allowing adhesive material to flow into thereservoir.

In another embodiment, an applicator device for dispensing apolymerizable adhesive material is provided. The applicator devicecomprises a body portion comprising a closed proximal end and an opendistal end providing a cavity. A plurality of breaking members areintegral with the body portion and each breaking member has asurrounding gap, the plurality of breaking members are at leastpartially deflectable into the cavity and each breaking member has afirst engagement member. At least one semi-rigid section sealablycontacts each of the plurality of breaking members and sealably coverseach corresponding surrounding gap. An annular housing iscircumferentially rotatable with respect to the body portion and has asecond engagement member complementary with the first engagement member,the first and the second engagement member being cooperativelyengageable with each other. A reservoir is secured to the open distalend of the body portion. The reservoir has a distal opening whichcomprises applicator means. A retaining member is located between thebody portion and the reservoir. A flow restrictor is proximal to thedistal opening of the reservoir. A frangible container of polymerizablemonomer adhesive material is disposed within the cavity between theclosed proximal end and the retaining member. When the annular housingis circumferentially rotated relative to the body portion from a firstposition where the first and the second engagement member are notcooperatively engaged with each other, to a second position where thefirst and the second engagement member are cooperatively engaged witheach other, at least a portion of the breaking member is deflected intothe cavity, breaking or piercing the frangible container and allowingadhesive material to flow into the reservoir.

In another embodiment, a method of applying/dispensing an adhesivematerial is provided. The method comprises providing an applicatordevice for dispensing and/or applying an adhesive material. Theapplicator device comprises a body portion comprising a closed proximalend and an open distal end providing a cavity. At least one breakingmember is integral with the body portion, each breaking member having asurrounding gap, and the at least one breaking member is at leastpartially deflectable into the cavity. Each breaking member has a firstengagement member. An annular housing is movable with respect to thebody portion and has a second engagement member complementary with thefirst engagement member, the first and the second engagement memberbeing cooperatively engageable with each other. A reservoir is securedto the open distal end of the body portion, the reservoir further havinga distal opening comprising applicator means. A retaining member islocated between the body portion and the reservoir and a frangiblecontainer of adhesive material is disposed within the cavity between theclosed proximal end and the retaining member. Moving the annular housingrelative to the body portion from a first position, where the first andthe second engagement members are not cooperatively engaged with eachother, to a second position where the first and the second engagementmembers are cooperatively engaged with each other, deflects at least aportion of the breaking member into the cavity breaking or piercing thefrangible container. Squeezing the reservoir provides a positivepressure within the reservoir, dispensing adhesive material from thereservoir to a substrate. Releasing the squeezed reservoir creates anegative pressure within the reservoir for urging adhesive material fromthe container within the cavity into the reservoir.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a top perspective view of an applicator deviceembodiment.

FIG. 2 is an exploded view of the embodiment as shown in FIG. 1.

FIG. 3 is an exploded view of the body portion of the embodiment asshown in FIG. 1.

FIG. 4 is a sectional view of the body portion and annular housingembodiment depicting non-engagement of corresponding engaging members ofan embodiment of FIG. 2.

FIG. 5 is a sectional view of body portion and annular housingembodiment depicting engagement of corresponding engaging members of anembodiment of FIG. 2.

FIG. 6 is a sectional view of body portion and annular housing depictingengagement of corresponding engaging members of an embodiment of FIG. 2.

FIG. 7 is a sectional view of an actuator embodiment.

FIG. 8 is a top plan view of a retaining member of the embodiment asshown in FIG. 2.

FIG. 9 is a top perspective view of an applicator device embodiment.

FIG. 10 is an exploded view of the embodiment as shown in FIG. 9

FIG. 11 is an exploded view of a body portion of the embodiment as shownin FIG. 9.

FIG. 12 is perspective view of a body segment of the embodiment as shownin FIG. 9.

DETAILED DESCRIPTION

In embodiments, an applicator and/or dispenser (herein after referred toas “applicator device”) is designed to facilitate manipulation by handfor mixing, dispensing and/or applying an adhesive or sealant material.For example, applicators and/or dispensers are provided that arepen-like, providing a familiar feel to the user. In embodiments, anapplicator is designed to reduce or eliminate leakage of adhesive fromthe device, be more securably gripped by the user, be more comfortableto the user, and/or easier to operate. The applicator allows for a“hands forward” position on the applicator device providing greatercontrol over placement of the adhesive or sealant material.Additionally, the placement and length of the actuator allows for easeof use of the applicator while maintaining the hands forward positionthereby allowing for greater control over the flow and direction of theadhesive or sealant material. In embodiments, the actuator may berecessed into the body portion such that it is flush to the body of theapplicator.

In particular, embodiments are directed to an applicator device fordispensing, mixing and/or applying an adhesive or sealant material,comprising: a body portion; a cavity in the body portion; an actuatormovable relative to the body portion; and at least one breaking memberintegral with the body portion and cooperatively engageable by theactuator, wherein movement of the actuator relative to the body portionmoves at least a portion of at least one breaking member into the cavityof the body portion.

In embodiments, the applicator device comprises a body portion. The bodyportion includes a closed proximal end and an open distal end whichforms a cavity within the body portion. The cavity may be sized toaccept a frangible container of adhesive or sealant material. The bodyportion may comprise one or more body segments. The closed distal endmay comprise re-sealable means such as a screw cap or snap-fit cap forinsertion of a frangible container at the point of use. The screw cap orsnap-fit cap preferably is designed to lock upon sealing with the bodyto prevent re-opening. The body portion or a body segment of the bodyportion may be molded or machined.

In various embodiments, the applicator device further comprises afrangible container of adhesive or sealant material at least partiallydisposed within the cavity, wherein movement of the actuator relative tothe body portion moves the breaking member(s) to rupture the frangiblecontainer.

In embodiments, the body portion or a body segment of the body portioncomprises at least one breaking member. The breaking member is formedfrom one or more surrounding gaps in the body portion. The breakingmember may be proximally integral with the body portion and distallyextend in a generally parallel direction with the longitudinal axis ofthe body portion. Alternatively, the breaking member may be distallyintegral with the body portion and proximally extend in a generallyparallel direction with the longitudinal axis of the body portion. Thebreaking member may be circumferentially integral with the body portion.The breaking member is deflectable such that at least a portion of thebreaking member enters the cavity. There may be only one breaking memberor there may be a plurality of breaking members. The term “plurality” asused herein refers to at least two. In embodiments, there are twobreaking members. The breaking members comprise a first engagementmember near or at their distal end. The first engagement member may be alobe, tine, protrusion, or equivalent. The first engagement member mayalternatively be a recess, cam race or equivalent. The breakingmember(s) may be positioned anywhere on the body portion or a bodysegment of the body portion such that upon deflection at least a portionof the breaking member(s) enters the cavity.

In embodiments, the applicator device comprises at least one semi-rigidsection. The semi-rigid section provides a seal such that adhesivematerial is restricted from leaking from the body portion of theapplicator device. The semi-rigid section sealably contacts each of theat least one breaking member and sealably covers each correspondingsurrounding gap. There may be a plurality of breaking members andcorresponding gaps that are contacted and sealed by a single semi-rigidsection. Alternatively, each breaking member and corresponding gap maybe contacted and sealed by a separate semi-rigid section. The semi-rigidportion provides a seal about the breaking member and the correspondinggap in the body portion reducing or eliminating leakage from the cavityafter the frangible container has been ruptured. In embodiments, thesemi-rigid portion sealably contacts the breaking members by essentiallyoverlaying the breaking member with the exception of at least a portionof the engagement member of the breaking member. This may be achieved byproviding an orifice such as a hole in the semi-rigid section foroutward protrusion of the engagement member of the breaking member. Thesemi-rigid portion is generally of a material less rigid than the bodyportion. The semi-rigid portion may be a thermoplastic elastomer. Thesemi-rigid section may be formed by co-injection molding, insert moldingor overmolding. In embodiments, the semi-rigid section may be formed outof the body portion or a body segment of the body portion, for example,as a thin-walled section.

In embodiments, the applicator device comprises an actuator. Inembodiments, the actuator comprises a movable annular housing or annularcollar. The terms “annular housing” and “annular collar” are used hereininterchangeably. The annular housing may contain a second engagementmember. The second engagement member of the movable annular housingengages at least one first engagement member of the breaking member. Thesecond engagement member is complementary with the first engagementmember. For example, when the first engagement member is a lobe, tine,protrusion, or equivalent, the second engagement member may be a cam,cam race or equivalent, or a thickened wall section. Alternatively, ifthe first engagement member is a cam, cam race or equivalent orthickened wall section, the second engagement member may be a lobe,tine, protrusion, or equivalent.

In embodiments, the actuator comprises an annular housing movablymounted on the body portion. The annular housing may becircumferentially rotatable or axially movably mounted on the bodyportion from a first position where the first and the second engagementmember are not cooperatively engaged with each other, to a secondposition where the first and the second engagement member arecooperatively engaged with each other such that the breaking member isdeflected into the cavity when the annular housing is in the secondposition. In embodiments, the annular housing is rotatablecircumferentially relative to the body portion from a first positionwhere the first and the second engagement member are not cooperativelyengaged with each other, to a second position where the first and thesecond engagement member are cooperatively engaged with each other suchthat the breaking member is deflected into the cavity when the annularhousing is in the second position. In embodiments, the annular housingis axially movable relative to the body portion from a first positionwhere the first and the second engagement member are not cooperativelyengaged with each other, to a second position where the first and thesecond engagement member are cooperatively engaged with each other suchthat the breaking member is deflected into the cavity when the annularhousing is in the second position. In embodiments, the annular housingis circumferentially rotatable and non-axially movable relative to thebody portion from a first position where the first and the secondengagement member are not cooperatively engaged with each other, to asecond position where the first and the second engagement member arecooperatively engaged with each other such that the breaking member isdeflected into the cavity when the annular housing is in the secondposition. By way of example, upon movement of the annular housing fromthe first position to the second position, the first and the secondengagement member are cooperatively engaged with each other such that atleast a portion of at least one breaking member is deflected into thecavity to rupture the frangible container. In embodiments, movement ofthe actuator relative to the body portion to move at least a portion ofthe breaking member into the cavity is inhibited prior to use of theapplicator device.

In embodiments, the applicator device further comprises a retainingmember at least partially disposed in the open distal end of the bodyportion. The retaining member may be positioned between the body portionand a reservoir. The retaining member directs flow of the polymerizableadhesive material from the body portion into the reservoir and/orprovides for venting. The retaining member restrains fragments of brokenfrangible container within the body portion. The retaining member ispreferably positioned proximal to the distal opening of the reservoir.The retaining member may be made of a material that is at least one ofporous, absorbent and adsorbent in nature. The retaining member may bemade of a wicking material. The retaining member may comprise a one-wayflow controlling element in combination with a venting element such thatair may easily or unimpededly enter the cavity as adhesive or sealantmaterial concurrently leaves the cavity. In embodiments, the retainingelement may comprise a plurality of orifices. For example, the retainingelement may comprise a generally centered orifice circumferentiallysurrounded by generally smaller orifices such that air may easily orunimpededly enter the cavity as adhesive or sealant materialconcurrently leaves the cavity.

In embodiments, the retaining member may further comprise a filter toprevent particles of the broken frangible container from exiting thecavity. The filter may be positioned between the retaining member andthe frangible container. Alternatively, the filter may be positionedsuch that the retaining member is between the filter and the frangiblecontainer. The filter may be integral with the retaining member. Thefilter may be any material or may be compatible or non-interactive withthe polymerizable adhesive material. By way of example, the filter maybe a screen or porous disk. By further way of example, the filter may beof polyethylene (e.g., high-density or ultra-high molecular weight),polyethylene terephthalate (PET), polypropylene, glass or metal etchedwith holes. In embodiments, at least one of a medicament, apolymerization initiator, a polymerization rate modifier and astabilizer for a polymerizable monomer is in or on the retaining memberand/or in or on the filter.

In embodiments, the applicator device further comprises a reservoirsecured to the open distal end of the body portion. The reservoir is influid communication with the cavity to receive the adhesive or sealantmaterial. The reservoir is essentially a hollow chamber which mayfunction as a reservoir, siphon and/or dispensing pump. The reservoirmay siphon adhesive from the cavity when released after squeezingbecause of a differential pressure that is caused by the recovery of thereservoir to its original shape. The reservoir may be flexible,semi-flexible, semi-rigid, reinforced or an exoskeleton. In embodiments,the reservoir is flexible. The reservoir may be of any material which iscompatible with the adhesive or sealant material such as polysilicones,KRATON®, polyurethanes, thermoplastic elastomer, and the like. Inembodiments, at least one of a medicament, a polymerization initiator, apolymerization rate modifier and a stabilizer for a polymerizablemonomer is in or on the reservoir. The reservoir may be molded, forexample, by liquid injection molding (LIM).

In embodiments, the applicator device further comprises applicator meanssuch as an applicator device tip that is connected to or integral withthe reservoir. In embodiments, the applicator means may comprise one ofa tube, a nozzle, a spatula, a rolling ball, a brush, and a swab. Inembodiments, the applicator means such as an applicator device tip isremovable and/or interchangeable. Examples of tips for applicators maybe found in U.S. Pat. Nos. 6,425,704 and 6,705,790, incorporated hereinby reference in their entireties.

In embodiments, the applicator device further comprises a flowrestrictor disposed in the reservoir proximal to the applicator devicetip, the flow restrictor providing a restricted flow of a material whenthe material is being dispensed from the reservoir. The flow restrictormay be frictionally secured proximal to the applicator device tip. Theflow restrictor may be a machined plug, which may contain an orifice.The flow restrictor preferably restricts flow more than the retainingmember and/or filter fluid path from the body portion to the reservoir.In embodiments, at least one of a medicament, a polymerizationinitiator, a polymerization rate modifier and a stabilizer for apolymerizable monomer is in or on the flow restrictor. In embodiments,at least one of a medicament, a polymerization initiator, apolymerization rate modifier and a stabilizer for a polymerizablemonomer is in or on the retaining member/filter, in or on the reservoir,in or on the flow restrictor, and/or in or on the applicator means.

In other embodiments, a method of applying/dispensing an adhesive orsealant material is provided. The method comprises providing anapplicator device including a container of adhesive or sealant materialat least partially in the cavity of the applicator device; moving anactuator relative to the body portion to deflect a breaking member torupture the container; squeezing a flexible reservoir to siphon theadhesive from the cavity; and dispensing the adhesive or sealantmaterial from the reservoir. In embodiments, the method furthercomprises applying the dispensed adhesive or sealant material to asubstrate to be bonded. The substrate may be any material requiringadhesive or sealant, including living tissue, particularly in medicalembodiments. The substrate may be a flexible material such as a mesh. Inembodiments, the mesh comprises at least one of a medicament, apolymerization initiator, a polymerization rate modifier and/or astabilizer for a polymerizable monomer and/or an adhesive material.

In other embodiments, the method comprises placing a container ofadhesive or sealant material at least partially into the cavity of anapplicator device; moving the actuator relative to the body portion todeflect the breaking member to rupture the container; squeezing theflexible reservoir to siphon the adhesive from the cavity and dispensingthe adhesive or sealant material from the reservoir.

In embodiments, the applicator device comprises a frangible containerthat includes one or more adhesive, or sealant materials. As usedherein, the terms “ampoule” and “cartridge” are used interchangeably andrefer to a frangible container capable of containing an adhesive oradhesive composition or sealant material. The term “frangible” in thecontext of a container refers generally to the ability of the containerto be readily or easily broken or ruptured such that the contents of thecontainer are released. The adhesive or sealant material may comprise apolymerizable monomeric adhesive or sealant material. In embodiments,the adhesive or sealant material comprises a polymerizable1,1-disubstituted ethylene monomer formulation. In embodiments, theadhesive or sealant material comprises a cyanoacrylate formulation. Inembodiments, synthetic adhesive materials such as polyurethane,polyethylene glycol, acrylates, glutaraldehyde and biologically basedadhesives may be used.

Monomers that may be used in the frangible container of theapplicator/dispenser are readily polymerizable, e.g. anionicallypolymerizable or free radical polymerizable, or polymerizable byzwitterions or ion pairs to form polymers. Some such monomers aredisclosed in, for example, U.S. Pat. No. 5,328,687 to Leung, et al.,which is hereby incorporated by reference in its entirety herein.Preferably, the cyanoacrylate adhesive compositions comprise one or morepolymerizable cyanoacrylate monomers and are biocompatible. The term“biocompatible” refers to a material being suited for and meeting therequirements of a medical device, used for either long or short termimplants or for non-implantable applications, such that when implantedor applied in an intended location, the material serves the intendedfunction for the required amount of time without causing an unacceptableresponse. Long term implants are defined as items implanted for morethan 30 days.

The cyanoacrylate adhesive compositions comprising one or morepolymerizable cyanoacrylate monomers may include combinations ormixtures of cyanoacrylate monomers.

By way of example, useful monomers include α-cyanoacrylates of formula(I). These monomers are known in the art and have the formula

wherein R² is hydrogen and R³ is a hydrocarbyl or substitutedhydrocarbyl group; a group having the formula —R⁴—O—R⁵—O—R⁶, wherein R⁴is a 1,2-alkylene group having 2-4 carbon atoms, R⁵ is an alkylene grouphaving 1-4 carbon atoms, and R⁶ is an alkyl group having 1-6 carbonatoms; or a group having the formula

wherein R⁷ is

wherein n is 1-10, preferably 1-5 carbon atoms, and R⁸ is an organicmoiety.

Examples of suitable hydrocarbyl and substituted hydrocarbyl groupsinclude straight chain or branched chain alkyl groups having 1-16 carbonatoms; straight chain or branched chain C₁-C₁₆ alkyl groups substitutedwith an acyloxy group, a haloalkyl group, an alkoxy group, a halogenatom, a cyano group, or a haloalkyl group; straight chain or branchedchain alkenyl groups having 2 to 16 carbon atoms; straight chain orbranched chain alkynyl groups having 2 to 12 carbon atoms; cycloalkylgroups; aralkyl groups; alkylaryl groups; and aryl groups.

The organic moiety R⁸ may be substituted or unsubstituted and may bestraight chain, branched or cyclic, saturated, unsaturated or aromatic.Examples of such organic moieties include C₁-C₈ alkyl moieties, C₂-C₈alkenyl moieties, C₂-C₈ alkynyl moieties, C₃-C₁₂ cycloaliphaticmoieties, aryl moieties such as phenyl and substituted phenyl andaralkyl moieties such as benzyl, methylbenzyl, and phenylethyl. Otherorganic moieties include substituted hydrocarbon moieties, such as halo(e.g., chloro-, fluoro- and bromo-substituted hydrocarbons) andoxy-substituted hydrocarbon (e.g., alkoxy substituted hydrocarbons)moieties. Preferred organic radicals are alkyl, alkenyl, and alkynylmoieties having from 1 to about 8 carbon atoms, and halo-substitutedderivatives thereof. Particularly preferred are alkyl moieties of 4 to 6carbon atoms.

In the cyanoacrylate monomer of formula (I), R³ may be an alkyl grouphaving 1-10 carbon atoms or a group having the formula -AOR⁹, wherein Ais a divalent straight or branched chain alkylene or oxyalkylene moietyhaving 2-8 carbon atoms, and R⁹ is a straight or branched alkyl moietyhaving 1-8 carbon atoms.

Examples of groups represented by the formula -AOR⁹ include1-methoxy-2-propyl, 2-butoxy ethyl, isopropoxy ethyl, 2-methoxy ethyl,and 2-ethoxy ethyl.

The α-cyanoacrylates of formula (I) may be prepared according to methodsknown in the art. U.S. Pat. Nos. 2,721,858 and 3,254,111, each of whichis hereby incorporated in its entirety by reference, disclose methodsfor preparing α-cyanoacrylates. For example, the α-cyanoacrylates may beprepared by reacting an alkyl cyanoacetate with formaldehyde in anonaqueous organic solvent and in the presence of a basic catalyst,followed by pyrolysis of the anhydrous intermediate polymer in thepresence of a polymerization inhibitor.

The α-cyanoacrylates of formula (I) wherein R³ is a group having theformula R⁴—O—R⁵—O—R⁶ may be prepared according to the method disclosedin U.S. Pat. No. 4,364,876 to Kimura et al., which is herebyincorporated in its entirety by reference. In the Kimura et al. method,the α-cyanoacrylates are prepared by producing a cyanoacetate byesterifying cyanoacetic acid with an alcohol or by transesterifying analkyl cyanoacetate and an alcohol; condensing the cyanoacetate andformaldehyde or para-formaldehyde in the presence of a catalyst at amolar ratio of 0.5-1.5:1, preferably 0.8-1.2:1, to obtain a condensate;depolymerizing the condensation reaction mixture either directly orafter removal of the condensation catalyst to yield crude cyanoacrylate;and distilling the crude cyanoacrylate to form a high puritycyanoacrylate.

The α-cyanoacrylates of formula (I) wherein R³ is a group having theformula

may be prepared according to the procedure described in U.S. Pat. No.3,995,641 to Kronenthal et al., which is hereby incorporated in itsentirety by reference. Examples of monomers of formula (I) includecyanopentadienoates and α-cyanoacrylates of the formula:

wherein Z is —CH═CH₂ and R³ is as defined above. The monomers of formula(II) wherein R³ is an alkyl group of 1-10 carbon atoms, i.e., the2-cyanopenta-2,4-dienoic acid esters, may be prepared by reacting anappropriate 2-cyanoacetate with acrolein in the presence of a catalystsuch as zinc chloride. This method of preparing 2-cyanopenta-2,4-dienoicacid esters is disclosed, for example, in U.S. Pat. No. 3,554,990, whichis hereby incorporated in its entirety by reference.

Suitable α-cyanoacrylate monomers which may be used, alone or incombination, include alkyl α-cyanoacrylates such as 2-octylcyanoacrylate; dodecyl cyanoacrylate; 2-ethylhexyl cyanoacrylate; butylcyanoacrylate such as n-butyl cyanoacrylate; ethyl cyanoacrylate; methylcyanoacrylate or other α-cyanoacrylate monomers such as methoxyethylcyanoacrylate; 2-ethoxyethyl cyanoacrylate; 3-methoxybutylcyanoacrylate; 2-butoxyethyl cyanoacrylate; 2-isopropoxyethylcyanoacrylate; and 1-methoxy-2-propyl cyanoacrylate. In embodiments, themonomers are ethyl, n-butyl, or 2-octyl α-cyanoacrylate. Othercyanoacrylate monomers which may be used include alkyl estercyanoacrylates, such as those prepared by the Knoevenagel reaction of analkyl cyanoacetate, or an alkyl ester cyanoacetate, withparaformaldehyde, subsequent thermal cracking of the resultant oligomerand distillation.

Monomers prepared with low moisture content and essentially free ofimpurities (e.g., surgical grade) are preferred for biomedical use.Monomers utilized for industrial purposes need not be as pure.

The alkyl ester cyanoacrylate monomers may have the formula:

wherein R^(1′) and R^(2′) are, independently, H, a straight, branched orcyclic alkyl, or are combined together in a cyclic alkyl group, R^(3′)is a straight, branched or cyclic alkyl group, and m is 1-8. Preferably,R^(1′) is H or a C₁, C₂ or C₃ alkyl group, such as methyl or ethyl;R^(2′) is H or a C₁, C₂ or C₃ alkyl group, such as methyl or ethyl;R^(3′) is a C₁-C₁₆ alkyl group, more preferably a C₁-C₁₀ alkyl group,such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, heptyl, octyl, nonyl or decyl, and even more preferably a C₂, C₃or C₄ alkyl group, and m is preferably 1-4.

Examples of the alkyl ester monomers may include, but are not limitedto:

Additional examples of alkyl ester cyanoacrylate monomers include, butare not limited to, butyl lactoyl cyanoacrylate (BLCA), butyl glycoloylcyanoacrylate (BGCA), isopropyl glycoloyl cyanoacrylate (IPGCA), ethyllactoyl cyanoacrylate (ELCA), and ethyl glycoloyl cyanoacrylate (EGCA)and combinations thereof. BLCA may be represented by the formula above,wherein R^(1′) is H, R^(2′) is methyl and R^(3′) is butyl. BGCA may berepresented by the formula above, wherein R^(1′) is H, R^(2′) is H andR^(3′) is butyl. IPGCA may be represented by the formula above, whereinR^(1′) is H, R^(2′) is H and R^(3′) is isopropyl. ELCA may berepresented by the formula above, wherein R^(1′) is H, R^(2′) is methyland R^(3′) is ethyl. EGCA may be represented by the formula above,wherein R^(1′) is H, R^(2′) is H and R^(3′) is ethyl.

Other examples of alkyl ester cyanoacrylate monomers include alkylalpha-cyanoacryloyl caprolactate and alkyl alpha-cyanoacryloylbutrylactate. Other cyanoacrylates useful in the present invention aredisclosed in U.S. Pat. No. 3,995,641 to Kronenthal et al., the entiredisclosure of which is hereby incorporated by reference.

Alternatively, or in addition, alkyl ether cyanoacrylate monomers may beused. Alkyl ethyl cyanoacrylates have the general formula:

wherein R^(1″) is a straight, branched or cyclic alkyl, and R^(2″) is astraight, branched or cyclic alkyl group. Preferably, R^(1″) is a C₁, C₂or C₃ alkyl group, such as methyl or ethyl; and R^(2″) is a C₁-C₁₆ alkylgroup, more preferably a C₁-C₁₀ alkyl group, such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonylor decyl, and even more preferably a C₂, C₃ or C₄ alkyl group.

Examples of alkyl ether cyanoacrylate monomers include, but are notlimited to, isopropyoxy ethyl cyanoacrylate (IPECA) and methoxy butylcyanoacrylate (MBCA) or combinations thereof IPECA may be represented bythe formula above, wherein R^(1″) is ethylene and R^(2″) is isopropyl.MBCA may be represented by the formula above, wherein R^(1″) isn-butylene and R^(2″) is methyl.

Alkyl ester cyanoacrylate monomers and alkyl ether cyanoacrylatemonomers are particularly useful for medical applications because oftheir absorbability by living tissue and associated fluids. The terms“absorbable” or “absorbable adhesive” or variations thereof refer to theability of a tissue-compatible material to degrade or biodegrade at sometime after implantation into products that are eliminated from the bodyor metabolized therein. Thus, as used herein, absorbability means thatthe polymerized adhesive is capable of being absorbed, either fully orpartially, by tissue after application of the adhesive.

Likewise, the terms “non-absorbable” or “non-absorbable adhesive” orvariations thereof refer to completely or substantially incapable ofbeing absorbed, either fully or partially, by tissue after applicationof the adhesive. Furthermore, relative terms such as “faster absorbing”and “slower absorbing” are used relative to two monomer species toindicate that a polymer produced from one monomer species is absorbedfaster (or slower) than a polymer formed from the other monomer species.

As used herein, the term “substantially absorbed” refers to at least 90%absorbed within about three years. Likewise, the term “substantiallynon-absorbed” means at most 20% absorbed within about three years.Preferably, 100% of the polymerized and applied cyanoacrylate when usingthese types of cyanoacrylate monomers may be absorbed in a period ofless than 3 years, preferably approximately 2-24 months, more preferably3-18 months, and most preferably 6-12 months after application of theadhesive to living tissue. The absorption time may vary depending on theparticular uses and tissues involved. Thus, for example longerabsorption time may be desired where the adhesive composition is appliedto hard tissues, such as bone, but a faster absorption time may bedesired where the adhesive composition is applied to softer tissues.

The selection of cyanoacrylate monomer will affect the absorption rateof the resultant polymer, as well as the polymerization rate of themonomer. Two or more different monomers that have varied absorptionand/or polymerization rates may be used in combination to give a greaterdegree of control over the absorption rate of the resultant polymer, aswell as the polymerization rate of the monomer.

The adhesive composition of the frangible container may comprise amixture of cyanoacrylate monomers species with varying absorption rates.Where two monomer species having different absorption rates are used, itis preferred that the absorption rates be sufficiently different that amixture of the two monomers may yield a third absorption rate that iseffectively different from the absorption rates of the two monomersindividually. Compositions according to these embodiments are described,for example, in U.S. patent application Ser. No. 09/919,877, filed Aug.2, 2001, published as U.S. Patent Publication No. 2002/0037310 on Mar.28, 2002, and U.S. Pat. No. 6,620,846, both incorporated herein byreference in their entireties.

Absorbable cyanoacrylate monomers have broad application for closure andhemostatic sealing of wounds and the like in various living tissue,including but not limited to internal organs and blood vessels. Theseabsorbable formulations may be applied on the interior or exterior ofvarious organs and tissues. Adhesives as disclosed are biocompatible andmay be applied internally or externally in or on living tissue.

For example, suitable adhesive compositions for the frangible containermay be prepared by mixing suitable quantities of an alkyl alphacyanoacrylate such as 2-octyl alpha-cyanoacrylate with one of butyllactoyl cyanoacrylate (BLCA), butyl glycoloyl cyanoacrylate (BGCA),isopropyl glycoloyl cyanoacrylate (IPGCA), ethyl lactoyl cyanoacrylate(ELCA), and ethyl glycoloyl cyanoacrylate (EGCA). Such mixtures mayrange from ratios of about 90:10 to about 10:90 by weight, preferablyabout 75:25 to about 25:75 by weight such as from about 60:40 to about40:60 by weight.

In embodiments, the applicator device may contain materials such as apolymerization initiator, accelerator, rate-modifier, and/orcross-linking agent for initiating polymerization and/or cross-linkingof the polymerizable monomer material. The polymerization initiator,accelerator, rate-modifier, and/or cross-linking agent may beincorporated into the retaining member and/or filter, the flowrestrictor and/or the reservoir of the applicator device.

Accelerated polymerization reduces the waiting time necessary afterapplication, and makes the adhesive composition more convenient toapply. Useful polymerization initiators or accelerators may includethose suitable for medical applications. For purposes herein, the phrase“suitable for medical application(s)” means that the polymerization ofthe monomer occurs in less than 5 minutes or less than 3 minutes,preferably in less than 2.5 minutes, more preferably in less than 1minute, and often in less than 45 seconds. Of course, the desiredpolymerization time can vary for different compositions and/or uses.Preferably, where absorbability is desired, a suitable initiator oraccelerator and a suitable monomer are selected to provide a polymerthat is substantially absorbed by a living organism in 2-24 months, suchas 3-18 months or 6-12 months after application of the adhesive toliving tissue. In embodiments where an initiator and/or accelerator isused, such agent is preferably located in a non-contacting relationshipwith the adhesive composition prior to use, so that prematurepolymerization of the adhesive composition does not occur.

Suitable initiators are known in the art and are described, for example,in U.S. Pat. Nos. 5,928,611 and 6,620,846, both incorporated herein byreference in their entireties, and U.S. Patent Application No.2002/0037310, also incorporated herein by reference in its entirety.Quaternary ammonium chloride and bromide salts useful as polymerizationinitiators are particularly suitable. By way of example, quaternaryammonium salts such as domiphen bromide, butyrylcholine chloride,benzalkonium bromide, acetyl choline chloride, among others, may beused.

Benzalkonium or benzyltrialkyl ammonium halides such as benzyltrialkylammonium chloride may be used in addition to one or more quaternaryammonium fluoride salts or one or more quaternary ammonium ether salts.When used, the benzalkonium halide may be benzalkonium halide in itsunpurified state, which comprises a mixture of varying chain-lengthcompounds, or it can be any suitable purified compound including thosehaving a chain length of from about 12 to about 18 carbon atoms,including but not limited to C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, and C₁₈compounds. By way of example, the additional initiator may be aquaternary ammonium chloride salt such as benzyltrialkyl ammoniumchloride (BTAC).

Other initiators or accelerators may also be selected by one of ordinaryskill in the art without undue experimentation. Such suitable initiatorsor accelerators may include, but are not limited to, detergentcompositions; surfactants: e.g., nonionic surfactants such aspolysorbate 20 (e.g., Tween 20™ from ICI Americas), polysorbate 80(e.g., Tween 80™ from ICI Americas) and poloxamers, cationic surfactantssuch as tetrabutylammonium bromide, anionic surfactants such as sodiumtetradecyl sulfate, and amphoteric or zwitterionic surfactants such asdodecyldimethyl(3-sulfopropyl)ammonium hydroxide, inner salt; amines,imines and amides, such as imidazole, arginine and povidine; phosphines,phosphites and phosphonium salts, such as triphenylphosphine andtriethyl phosphite; alcohols such as ethylene glycol, methyl gallate;tannins; inorganic bases and salts, such as sodium bisulfite, calciumsulfate and sodium silicate; sulfur compounds such as thiourea andpolysulfides; polymeric cyclic ethers such as monensin, nonactin, crownethers, calixarenes and polymeric-epoxides; cyclic and acycliccarbonates, such as diethyl carbonate; phase transfer catalysts such asAliquat 336; organometallics such as cobalt naphthenate and manganeseacetylacetonate; and radical initiators or accelerators and radicals,such as di-t-butyl peroxide and azobisisobutyronitrile.

In embodiments, anti-microbial or therapeutic agents may be includedwith the polymerization adhesive composition.

In embodiments where monomer additives including, but not limited tothose listed above, are insoluble with the monomer composition and/orthat would cause premature polymerization of the monomer, the additivemay be applied to the application site before applying the monomercomposition. In such embodiments, the additive may be provided, forexample, in separate packages in a kit.

In other embodiments, where such additives are soluble with thepolymerizable adhesive composition and/or would not cause prematurepolymerization, the additives may be combined with the polymerizableadhesive composition during its manufacture.

The additive may be mixed immediately prior to use upon rupture of thecartridge, ampoule or ampoules by activation of the annular collar orhousing. Alternatively, mixing may be conducted in the reservoir and/orduring the application process, for example, which thereby mixes theadditive with the adhesive composition during application. In addition,as discussed above with respect to suitable anti-microbial andtherapeutic agents, other additives may serve as stabilizers for theadhesive composition.

The adhesive composition may optionally include at least oneplasticizing agent that assists in imparting flexibility to the polymerformed from the polymerizable adhesive composition. The plasticizingagent preferably contains little or no moisture and should notsignificantly affect the stability or polymerization of thepolymerizable adhesive composition. Examples of suitable plasticizersinclude acetyl tributyl citrate, dimethyl sebacate, dibutyl sebacate,triethyl phosphate, tri(2-ethylhexyl)phosphate, tri(p-cresyl)phosphate,glyceryl triacetate, glyceryl tributyrate, diethyl sebacate, dioctyladipate, isopropyl myristate, butyl stearate, lauric acid, trioctyltrimellitate, dioctyl glutarate, polydimethylsiloxane, and mixturesthereof. Preferred plasticizers may include tributyl citrate, acetyltributyl citrate or dibutyl sebacate. In embodiments, suitableplasticizers include polymeric plasticizers, such as polyethylene glycol(PEG) esters and capped PEG esters or ethers, polyester glutarates andpolyester adipates, as well as others as listed in U.S. Pat. No.6,183,593, the disclosure of which is incorporated in its entirety byreference herein.

The adhesive composition may also optionally include at least onethixotropic agent. Suitable thixotropic agents are known to the skilledartisan and include, but are not limited to, silica gels such as thosetreated with a silyl isocyanate, and optionally surface treated titaniumdioxide. Examples of suitable thixotropic agents and thickeners aredisclosed in, for example, U.S. Pat. No. 4,720,513, and U.S. Pat. No.6,310,166, the disclosures of which are hereby incorporated in theirentireties by reference herein.

The adhesive composition may optionally also include thickeners.Suitable thickeners may include poly (L-lactide-co-caprolactone),poly(2-ethylhexy methacrylate), poly(2-ethylhexyl acrylate) and othersas listed in U.S. Pat. No. 6,673,192, the disclosure of which isincorporated by reference herein in its entirety.

The adhesive composition may also optionally include at least onenatural or synthetic rubber to impart impact resistance. Suitablerubbers are known to the skilled artisan. Such rubbers include, but arenot limited to, dienes, styrenes, acrylonitriles, and mixtures thereof.Examples of suitable rubbers are disclosed in, for example, U.S. Pat.Nos. 4,313,865 and 4,560,723, the disclosures of which are herebyincorporated in their entireties by reference herein.

The adhesive composition may optionally also include one or morestabilizers, including one or more free radical stabilizers and/or oneor more anionic stabilizers, preferably both at least one anionic vaporphase stabilizer and at least one anionic liquid phase stabilizer. Thesestabilizing agents may inhibit premature polymerization. Suitablestabilizers may include those listed in U.S. Pat. No. 6,183,593, thedisclosure of which is incorporated by reference herein in its entirety.Furthermore, certain stabilizers may also function as anti-microbialagents, such as, for example, various acidic anti-microbials, asidentified above.

The stability, and thus the shelf-life, of some monomeric adhesivecompositions may be further enhanced and extended through carefulregulation of the ampoule. Treated (e.g., fluorinated polymer) glassampoules may reduce the amount of stabilizer that is combined into theadhesive composition. As mentioned above, certain stabilizers including,but not limited to, certain acidics may also function as anti-microbialagents. In this case, the amount of the anti-microbial/stabilizermaterial is either not reduced below a level to provide the desiredanti-microbial effect, or a further anti-microbial/non-stabilizing agentis added to ensure that the desired anti-microbial effect is provided.

The adhesive compositions may also include pH modifiers to control therate of degradation of the resulting polymer, as disclosed in U.S. Pat.No. 6,143,352, the entire disclosure of which is hereby incorporated byreference herein in its entirety.

To improve the cohesive strength of adhesives formed from the adhesivecompositions applicable to the applicator device herein described,difunctional monomeric cross-linking agents may be added to the monomercompositions. Such crosslinking agents include those as disclosed inU.S. Pat. No. 3,940,362, which is hereby incorporated herein in itsentirety by reference, discloses exemplary cross-linking agents.

The adhesive compositions of this invention may further contain fibrousreinforcement and colorants such as dyes, pigments, and pigment dyes.Examples of suitable fibrous reinforcement include PGA microfibrils,collagen microfibrils, and others as described in U.S. Pat. No.6,183,593, the disclosure of which is incorporated by reference hereinin its entirety.

The polymerizable compositions useful in the present invention may alsofurther contain one or more preservatives, for prolonging the storagelife of the adhesive composition. Suitable preservatives, and methodsfor selecting them and incorporating them into adhesive compositions,are disclosed in U.S. Pat. No. 6,579,469, the entire disclosure of whichis incorporated herein by reference.

In embodiments, the adhesive applicator, including its monomercomposition and/or its packaging may be sterilized. However,sterilization is not required, particularly in view of the fact that theadhesive composition will be used on open wounds. Furthermore, whetheror not the applicator is sterilized, the applicator adhesive compositionmay further include one or more suitable preservatives, as describedbelow.

Sterilization of the applicator monomer composition and/or its packagingmay be accomplished by techniques known to the skilled artisan, and ispreferably accomplished by methods including, but not limited to,chemical, physical, and/or irradiation methods. Examples of chemicalmethods include, but are not limited to, exposure to ethylene oxide orhydrogen peroxide vapor. Examples of physical methods include, but arenot limited to, sterilization by heat (dry or moist) or retort canning.Examples of irradiation methods include, but are not limited to, gammairradiation, electron beam irradiation, and microwave irradiation. Apreferred method is electron beam irradiation, as described in U.S. Pat.No. 6,143,805, the entire disclosure of which is incorporated herein byreference. The different components or groups of components of theapplicator may be sterilized separately before packaging or assembly ofthe components or groups of components, and/or the different componentsor groups of components may be sterilized after assembly or packaging asis disclosed in co-assigned U.S. Pregrant Patent Publication No.2004/0120849, which is hereby incorporated herein in its entirety byreference. The materials of the applicator and/or the adhesivecomposition should also show low levels of toxicity to living tissueduring its useful life. In preferred embodiments of the presentinvention, the applicator and/or adhesive composition is sterilized toprovide a Sterility Assurance Level (SAL) of at least 10⁻³. Inembodiments, the Sterility Assurance Level may be at least 10, or may beat least 10⁻⁵, or may be at least 10⁻⁶.

The materials used for the construction of the applicator device maycontain antimicrobials which migrate to the surface of the applicatordevice to provide antimicrobial action or prevent or eliminate microbialcolonization during use. Such antimicrobials include, but are notlimited to, triclosan, chlorhexidine, silver sulfadiazine, silver salts,hinokitiol, benzalkonium chloride and zinc pyrithione. Antimicrobialsmay be added to the materials comprising the applicator device such asthe body portion, reservoir and/or actuator during the molding processor may be impregnated or applied after the applicator device or itscomponents are molded, and includes impregnation or application beforeor after assembly.

In addition to the various advantages identified above, the applicatordevice and methods of using same provide additional advantages overstate-of-the art adhesive application protocols. For example, anadvantage of using the applicator in combination with a polymerizableadhesive compositions such as monomeric cyanoacrylate is that theadhesive compositions polymerize on contact with the site, forming anocclusive dressing and creating a moist wound environment conducive tohealing. Healing of such injured site is thus expected to be quicker andmore natural than for other treatment protocols. Furthermore, thisocclusive coating protects the site from further injury while alsofunctioning as a microbial barrier.

Still further, the present invention provides adhesive applicationprotocols that are considered advantageous both to the healthcareprofessional and the patient. In the clinical scenario, use ofapplicator containing topically applied polymerizable adhesivecompositions, such as monomeric cyanoacrylate, in frangible ampoules maypose the possibility of leakage of the adhesive from the applicatorremote from the wound site. The applicator herein described provides forsealed containment of the adhesive and improved control of itsapplication at the wound site.

In embodiments, the applicator device may be used and/or packaged incombination with a flexible material such as a mesh. The flexiblematerial may comprise a polymerization initiator or rate modifierdisposed in or on the flexible material. The applicator device mayprovide for the polymerizable adhesive composition to be applied andpermeated throughout at least a portion of the flexible material, wherethe polymerization initiator or rate modifier is a polymerizationinitiator or rate modifier for the polymerizable adhesive composition.The flexible material may be a tissue bonding article for bonding tissuesurfaces, or may be used in other applications.

The flexible material may be applied to a surface, and impregnated witha polymerizable monomeric adhesive composition from the applicatordevice, which upon setting or curing provides an adherent structure overthe surface. Polymerization (setting or curing) of the polymerizablemonomeric adhesive composition is assisted by the flexible materialbeing loaded, coated, or the like with a polymerization initiator orrate modifier for the polymerizable monomeric adhesive composition.

The flexible material preferably includes one or more chemical materialslocated within the flexible material. For example, one or more chemicalsubstances may be dispersed in the flexible material, such as beingchemically bound, physically bound, absorbed, or adsorbed to theflexible material. Thus, for example, the flexible material preferablyincludes at least a polymerization initiator or rate modifier, and mayoptionally include one or more bioactive materials. As desired, the oneor more chemical substances may be either immobilized on or in theflexible material, for example, so that it has a desired effect but isnot detached from the flexible material during use, or it may beattached to the flexible material in a manner such that it becomesdetached during use.

For example, a polymerization initiator or rate modifier may be loadedon the flexible material so that the initiator or rate modifier providesthe desired initiation or rate modification effect to a subsequentlyapplied polymerizable adhesive composition. The polymerization initiatoror rate modifier may be immobilized on the flexible material, so thatthe initiator or rate modifier does not become detached from theflexible material and its residues dispersed in the resultant polymericmaterial. Alternatively, for example, the polymerization initiator orrate modifier may be initially attached to the flexible material, butonly in such a manner that it becomes mobilized or solubilized by asubsequently applied polymerizable adhesive composition and dispersed inthe resultant polymeric material.

If desired, a combination of chemical substances may also be provided onthe flexible material, to provide multiple effects. For example, asdescribed above, a first chemical species (such as a polymerizationinitiator or rate modifier) may be immobilized on the flexible material,while a second, different chemical species (such as a bioactivematerial) may be detachably attached to the flexible material. Othercombinations of chemical species and resultant effects are alsoenvisioned.

When present in or on the flexible material, the chemical substances(i.e., polymerization initiator, rate modifier, and/or bioactivematerials, or other additives), may be incorporated in or on theflexible material in any suitable manner. For example, the chemicalsubstance may be added to the flexible material by contacting theflexible material with a solution, mixture, or the like including thechemical substances. The chemical substance may be added to the flexiblematerial, for example, by dipping, spraying, roll coating, gravurecoating, brushing, vapor deposition, or the like. Alternatively, thechemical substance may be incorporated into or onto the flexiblematerial during manufacture of the flexible material, such as duringmolding or the like of the flexible material.

The chemical substance may be present in or on the flexible material inany suitable concentration and manner. For example, the chemicalsubstance may be applied in a uniform manner to the flexible material,such that there is a substantially uniform concentration of the chemicalsubstance across the flexible material. Alternatively, the chemicalsubstance may be applied such that a concentration gradient existsacross or through the flexible material. For example, a greater orsmaller concentration of the chemical substance could exist at thecenter or edges of the flexible material, or a greater or smallerconcentration of the chemical substance could be applied on one side ofthe flexible material as compared to an opposite side. Further, thechemical substance may be applied in a uniform manner to the flexiblesubstrate, or it may be applied in a non-uniform random or patternedmanner (such as lines, dots, concentric circles, or the like).

Other chemical substances that may be present in or on the flexiblematerial include, but are not limited to, any suitable and preferablycompatible additive that enhances performance of the compositestructure. Such additional chemical substances may be bioactive ornon-bioactive. Suitable other chemical substances thus include, but arenot limited to, colorants (such as inks, dyes and pigments), scents,protective coatings that do not chemically detach, temperature sensitiveagents, drugs, and the like.

The polymerization initiator or rate modifier loaded on the flexiblematerial may provide a number of advantages for example, the tailoringof the setting or polymerization time of the applied polymerizableadhesive composition. For example, the type and/or concentration ofinitiator that is applied to the flexible material may be selected so asto provide faster or slower polymerization time. The concentration ofpolymerization initiator or rate modifier may be increased to provide afaster polymerization time, or may be decreased to provide a slowerpolymerization time.

Because the polymerization initiator or rate modifier is loaded directlyon the flexible material, it is not necessary to mix the polymerizableadhesive composition with a polymerization initiator or rate modifier inan applicator prior to application. Thus, the applicator devicecontaining the polymerizable adhesive composition may avoid or eliminatebecoming plugged and unusable by polymerizable adhesive compositionpolymerizing in an applicator tip. This may allow a longer working time,where the polymerizable monomer composition may be more precisely andcarefully applied over a longer period of time.

The flexible material may trap or act as a barrier to flow of thepolymerizable adhesive composition during application, therefore theremay be less running of the adhesive composition away from theapplication site. In addition, where one or more chemical substances arepresent in or on the flexible material, such chemical substances may bemore specifically or precisely applied. For example, the chemicalsubstances may be applied to the flexible material only at specificlocations, or in a gradient pattern, if desired, which may provide astronger composite structure than is provided by a polymerizableadhesive composition alone.

The flexible or compliant material may be formed of any suitableflexible or compliant material. Preferably, the flexible or compliantmaterial is a material that is flexible, porous, and non-toxic. Suitableflexible materials are as described in co-assigned U.S. Pregrant PatentApplication No. 2006/0009099, incorporated herein by reference in itsentirety.

The flexible material is preferably flexible or compliant, to allow theflexible substrate to be placed on the desired surface (such as skin,organ, tissue, or the like) in a manner that allows the flexiblesubstrate to conform to the topology of the desired surface. Likewise,the flexible material is preferably porous, to allow the subsequentlyapplied polymerizable adhesive material to pass through or permeatethrough the flexible material and to polymerize as a layer beneath theflexible material, while adhering the flexible material to the desiredsubstrate. By “porous” is meant herein either that the bulk of theflexible material has pores, such that the subsequently appliedpolymerizable adhesive material is soaked up or absorbed by the bulkmaterial, or that the bulk of the flexible material has voids (like anet or screen), such that the subsequently applied polymerizableadhesive material passes directly through the bulk material, with orwithout being soaked up or absorbed by the bulk material. For example,in the case of textile materials, “porous” is generally used to meanthat the applied adhesive composition permeates and passes throughinterstices between the fibers, but does not necessarily pass into andthrough the fibers themselves.

Such porosity (or other properties such as hydrophobicity orhydrophilicity) will also allow a polymerization initiator or ratemodifier to be loaded on the flexible material prior to use, to initiatethe subsequently applied polymerizable adhesive material. Such porositywill also preferably allow air and water to pass through the flexiblematerial (either through pores per se, or through voids in the bulkmaterial). Depending upon the degree of porosity (and/or the size of theopenings), such porosity of the flexible material or ability of air andwater to permeate through the flexible material may be tailored toeither remain after a final composite material is formed, or to beabsent therefrom. The flexible material is also preferably non-toxic, asit is intended to be used as a wound covering, such as on biologicaltissues. As such, the flexible material should be biologicallycompatible with the desired substrate (such as tissue, skin, organ, orthe like), and is preferably a material that is governmentally approvedor generally regarded as safe for the desired purpose.

In embodiments, the flexible material is a textile or mesh/web material.Suitable textile materials may be formed of either synthetic or naturalmaterials. Such textile material may be formed of either woven ornon-woven fabrics or materials. The flexible material may be, forexample, any suitable polymeric film, plastic foam (including opencelled foam), a woven fabric, knitted fabric, a non-woven fabric,mixture thereof, or the like. In particular, suitable flexible materialsmay thus be prepared, for example, from nylon, a polyolefin film, suchas polyethylene, polypropylene, ethylene propylene copolymers, andethylene butylene copolymers, polyurethanes, polyurethane foams,polystyrenes, plasticized polyvinylchlorides, polyesters, polyamides,polylactic acid, polyglycolic acid, polycaprolactone, copolymer mixturesof the above, and cotton. Suitable specific examples include, forexample, nylon, polyethylene, polypropylene, ethylene propylenecopolymers, ethylene butylene copolymers, polyurethane, polystyrene,plasticized polyvinylchloride, polyester, polyamide, cotton,polytetrafluoroethylene (PTFE), biovascular material, collagen,Gore-Tex®, DACRON®, etc.

The flexible material may be formed of a synthetic, semi-synthetic, ornatural organic material. Thus, for example, the flexible material maybe formed of a synthetic or natural polymer material, but not from amaterial such as metal (such as silver, steel or the like) or glass orceramic. The flexible material may be either biodegradable, or notbiodegradable. The flexible material is preferably resistant to tearing.The thickness of the flexible material may be from about 0.1 mil toabout 80 mils. In another embodiment, the thickness of the flexiblematerial is from about 0.5 mil to about 20 mils, preferably from about0.7 mil to about 10 mils, or from about 1 mil to about 5 mils.

The size of the flexible material may be tailored for specific intendeduses, or it may be provided in a sheet or roll form or any suitableshape or dimension of the flexible material may be provided. Theflexible material may be provided in a dispenser. The flexible materialis not limited to any particular dimensions, and the dimensions (length,width, thickness, etc.) of the flexible material may be varied andtailored, as desired.

In some embodiments, the flexible material can include a pressuresensitive adhesive on at least one face, by way of example, to assist ininitial placement of the flexible material on the desired surface. Inembodiments where the flexible material includes a pressure sensitiveadhesive applied to portions of the flexible material, the pressuresensitive adhesive can be applied to an entire surface of the flexiblematerial, or only to portions (such as peripheral edges) of the surfaceof the flexible material. The exposed pressure sensitive adhesive can becovered by a suitable release layer or liner, if desired, to preservethe adhesiveness of the flexible material until time of use. Thepressure sensitive adhesive, if present, can be applied in the variousmanners shown in U.S. Patent Application Publication No. 2005/0182443,the entire disclosure of which is incorporated herein by reference.

In embodiments, a method of bonding tissue is provided. The methodcomprises placing a flexible material over a substrate, the flexiblematerial comprising a polymerization initiator or rate modifier disposedin or on the flexible material. The applicator device as hereindescribed applies a polymerizable adhesive composition over andsubstantially covering at least a portion of the flexible material. Thepolymerizable adhesive composition is allowed to permeate into and underthe flexible material and polymerize to form a composite structurebonded to the substrate. The substrate may be tissue. The tissue may behard tissue (such as bone) or soft tissue (such as skin, organs, mucousmembranes, and the like). The tissue may be either internal or external.

In other embodiments, a kit is provided. The kit comprises: at least oneapplicator device as herein described; and optionally one or morecontainers of adhesive or sealant material arranged to be placed atleast partially in the cavity of the at least one applicator device,wherein movement of the actuator relative to the body portion deflectsthe breaking member to rupture one of the containers that is placed atleast partially in the cavity. In embodiments, the kit further comprisesa plurality of removable and/or interchangeable applicator tips. Inembodiments, the kit further comprises a flexible material/mesh whichmay be loaded with polymerization initiator or rate modifier for theadhesive or sealant material. The different components or groups ofcomponents may be sterilized in separate containers before packaging thecomponents or groups of components within a kit, and thereaftersterilizing the kit as disclosed in co-assigned U.S. Pregrant PatentPublication No. 2004/0120849.

Various other features and advantages of the embodiments of theinvention will be apparent from the following description of exemplaryembodiments and figures.

Referring to FIG. 1, applicator device 10 includes body portion 100having a closed proximal end 110. Actuator 300 includes annular collar301, which mechanically secures body portion 100 with reservoir 600.Reservoir 600 includes distal applicator tip 620 for dispensing ofadhesive.

Referring now to FIG. 2, applicator device 10 includes frangiblecontainer 200, which is contained in body 100 and in proximity tobreaking member 135 of body portion 100. Semi-rigid section 800 overlaysbreaking member in sealable contact therewith. Filter 400 and retainingmember 500 separate frangible container 200 from reservoir 600.Reservoir 600 includes flow restrictor 700, which is frictionallysecured at reservoir 600 distal end of applicator tip 620.

Referring now to FIG. 3, breaking member 135 of body portion 100 ispositioned in surrounding gap 115 between closed proximal end 110 andopen distal end 120 to provide for deflection into the cavity. Firstengagement member 125 of breaking member 135 projects outwardly from thebody portion. Semi-rigid section 800 seals surrounding gap 115 andsealably contacts breaking member 135 via section 835. Semi-rigidsection 800 includes orifice 825 for exposing first engagement member125 through the semi-rigid section. Undercut 140 in body portion 100accepts and mates with protrusions 840 of semi-rigid section 800 toprovide leak-resistant sealing.

Referring to FIGS. 3, 4 and 5, forward tapered collar 160 with undercut165 provides for accepting the reservoir flange 605 into recess 170which may extend up to and abut forward lip 180. Reservoir 600 ismechanically secured to body portion 100 between annular collar 401 andrecess 170 and forward tapered collar 160. Annular groove 430 ofactuator 400 receives annular rib 130 of body portion 100 to secure theactuator on body portion.

Still referring to FIGS. 4 and 5, the first and second positions of theactuator are depicted. In a first position, second engagement members425 (not shown) of annular collar 401 are disengaged with the firstengagement members 125 of breaking members 135, as shown in FIG. 4. In asecond position, second engagement members 425, shown as a thickenedwall section, of annular collar 401 are engaged with first engagementmembers 125 of breaking members 135 causing deflection of the breakingmembers into frangible container 200 in the cavity 50 as shown in FIG.5. Deflection into the cavity is such that a frangible container 200would be ruptured to release its contents. Body portion indexing marker150 provides for indexing of actuator 400 for assembly without engagingfirst and second engagement members. During assembly, annular groove 430snaps over annular rib 130 and then upon assembly relaxes around annularrib 130 as shown assembled in FIG. 5. Sectional view of actuator 400, asshown in FIG. 7, depicts indexing track element 475 for positioning andreceiving indexing body portion indexing marker 150 during assembly.

Referring now to FIG. 6, a second position of an embodiment of anactuator is depicted. In a second position, second engagement members425A, shown as cam elements, of annular collar 401A are engaged withfirst engagement members 125 of breaker members 135 causing deflectionof the breaking members into the frangible container 200 in the cavity50. Deflection into the cavity is such that a frangible container 200would be ruptured to release its contents, as shown in FIG. 6.

Referring now to FIG. 8, an exemplary retaining member 500 includesorifices 525 and larger orifice 550. Orifices 525 alone or incombination with filter 400 provide retention of the frangible container200 within the cavity while larger orifice 550 provides for concurrentventing of the cavity.

Referring now to FIGS. 9-12, dispenser 10A includes body portion 100A,which includes forward body segment 194 and rearward body segment 192,as shown in FIG. 11 (annular housing not shown). Forward body segment194 including breaking member 135 is received by rearward body segment192 with cooperative alignment means 103 and 101. Retaining member 500is positioned within forward body segment 194 securing frangiblecontainer 200 into body portion 100A. Reservoir 600 includes flowrestrictor 700 frictionally secured at the distal end of the reservoir.By way of example, dispenser 10A may be assembled by receiving forwardbody segment 194 into rearward body segment 192 with cooperativealignment means 103 and 101, placing the open proximal end of reservoir600 over recess 170 of forward body segment 194 and sliding actuator 900over forward body segment 194. Forward and rearward body segments 194,192 of body portion 100A may be secured by placing a solvent or adhesivein one of securing orifices 199 in rearward body segment 192, forexample, using a syringe, until solvent or adhesive comes out of theother orifice.

While the invention has been described with reference to preferredembodiments, the invention is not limited to the specific examplesgiven, and other embodiments and modifications may be made by thoseskilled in the art without departing from the spirit and scope of theinvention. Thus, while this invention has been described in terms ofexemplary embodiments, it is to be understood that this invention is notto be limited to the particular configuration of these embodiments. Oneskilled in the art will recognize that various modifications and/oralterations of these embodiments may be made while remaining within thescope of this invention.

1. A method of applying/dispensing an adhesive material, the methodcomprising: providing an applicator device for dispensing and/orapplying an adhesive material, the applicator device comprising: a bodyportion comprising a closed proximal end and an open distal endproviding a cavity; at least one breaking member integral with the bodyportion and each breaking member having a surrounding gap, the at leastone breaking member at least partially deflectable into the cavity andeach breaking member having a first engagement member; an annularhousing movable with respect to the body portion and having a secondengagement member complementary with the at least one first engagementmember, the first and the second engagement member being cooperativelyengageable with each other; a reservoir secured to the open distal endof the body portion, the reservoir further having a distal openingcomprising applicator means, a retaining member between the body portionand the reservoir; and a frangible container of adhesive materialdisposed within the cavity between the closed proximal end and theretaining member; moving the annular housing relative to the bodyportion from a first position where the first and the second engagementmember are not cooperatively engaged with each other, to a secondposition where the first and the second engagement member arecooperatively engaged with each other, deflecting at least a portion ofthe breaking member into the cavity breaking the frangible container;squeezing the reservoir providing a positive pressure within thereservoir and dispensing adhesive material from the reservoir to asubstrate; wherein releasing the squeezed reservoir creates a negativepressure within the reservoir for urging of the adhesive material fromthe cavity into the reservoir.
 2. The method of claim 1, wherein thesubstrate is living tissue, a flexible material or mesh.
 3. The methodof claim 2, wherein the flexible material or mesh comprises at least oneof a medicament, a polymerization initiator or polymerization ratemodifier for the adhesive material.
 4. The method of claim 2, whereinthe applicator device, the frangible container of adhesive materialand/or the adhesive material is sterilized.